INTRODUCTION: Cluster of differentiation 36 (CD36) is highly expressed in the liver of patients with metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH). However, the precise role of CD36 in MAFLD/MASH is controversial. In the current study, we aimed to uncover the role of CD36 in the early stage of MAFLD/MASH induced by high-fat diet (HFD) and methionine/choline-deficient (MCD) diet. METHODS: CD36 RESULTS: We determined that CD36 deficiency attenuated HFD-induced hepatic steatosis while exacerbating MCD diet-induced steatohepatitis. Mechanistically, CD36 deficiency reduced HFD-induced expression of fatty acid synthase (FASN), sterol regulatory element binding protein 1c (SREBP1c), and acetyl-CoA carboxylase alpha (ACC1), thereby inhibiting de novo fatty acid synthesis. The expression of superoxide dismutase and genes involving fatty acid oxidation was inhibited by MCD diet. CD36 deficiency reduced expression of genes involving fatty acid oxidation, while MCD diet had no effect on these genes expression in CD36 DISCUSSION: CD36 deficiency improves HFD-induced MAFLD by inhibiting fatty acid synthesis, while accelerating MCD diet-induced MASH via promoting Cer, LPC, TG and DG accumulation to accelerate liver inflammation. The complex role of CD36 in MAFLD/MASH needs more investigation to discover the precise and effective strategy when targeting CD36.